NM_018129.4:c.552G>A

Variant names:

• chr17-47946328-G-A
• rs4378657
• NM_018129.4:c.552G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_018129.4(PNPO):​c.552G>A​(p.Leu184Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0738 in 1,610,284 control chromosomes in the GnomAD database, including 4,933 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.064 (366 hom., cov: 32)
  • Exomes 𝑓: 0.075 (4567 hom.)
• Consequence: PNPO NM_018129.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.967
• Publications: 17 publications found

Genes affected

PNPO (HGNC:30260): (pyridoxamine 5'-phosphate oxidase) The enzyme encoded by this gene catalyzes the terminal, rate-limiting step in the synthesis of pyridoxal 5'-phosphate, also known as vitamin B6. Vitamin B6 is a required co-factor for enzymes involved in both homocysteine metabolism and synthesis of neurotransmitters such as catecholamine. Mutations in this gene result in pyridoxamine 5'-phosphate oxidase (PNPO) deficiency, a form of neonatal epileptic encephalopathy. [provided by RefSeq, Oct 2008]

PNPO Gene-Disease associations (from GenCC):

• pyridoxal phosphate-responsive seizures

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet, ClinGen

ENSG00000263798 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.37).
• BP6: Variant 17-47946328-G-A is Benign according to our data. Variant chr17-47946328-G-A is described in ClinVar as Benign. ClinVar VariationId is 129983.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.967 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0821 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018129.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PNPO	NM_018129.4	MANE Select	c.552G>A	p.Leu184Leu	synonymous	Exon 6 of 7	NP_060599.1	Q9NVS9-1
	PNPO	NM_001436305.1		c.423G>A	p.Leu141Leu	synonymous	Exon 5 of 6	NP_001423234.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PNPO	ENST00000642017.2	MANE Select	c.552G>A	p.Leu184Leu	synonymous	Exon 6 of 7	ENSP00000493302.2	Q9NVS9-1
	PNPO	ENST00000225573.5	TSL:1	c.423G>A	p.Leu141Leu	synonymous	Exon 5 of 6	ENSP00000225573.5	Q9NVS9-4
	PNPO	ENST00000434554.7	TSL:2	c.498G>A	p.Leu166Leu	synonymous	Exon 5 of 6	ENSP00000399960.3	Q9NVS9-3

Frequencies

GnomAD3 genomes AF: 0.0636 AC: 9668 AN: 152080 Hom.: 365 Cov.: 32

Gnomad AFR AF: 0.0315

Gnomad AMI AF: 0.0297

Gnomad AMR AF: 0.0585

Gnomad ASJ AF: 0.0985

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.0886

Gnomad FIN AF: 0.0915

Gnomad MID AF: 0.0854

Gnomad NFE AF: 0.0812

Gnomad OTH AF: 0.0728

GnomAD2 exomes AF: 0.0685 AC: 17168 AN: 250688 AF XY: 0.0721

Gnomad AFR exome AF: 0.0311

Gnomad AMR exome AF: 0.0413

Gnomad ASJ exome AF: 0.0935

Gnomad EAS exome AF: 0.000272

Gnomad FIN exome AF: 0.0864

Gnomad NFE exome AF: 0.0803

Gnomad OTH exome AF: 0.0733

GnomAD4 exome AF: 0.0749 AC: 109163 AN: 1458086 Hom.: 4567 Cov.: 30 AF XY: 0.0764 AC XY: 55453 AN XY: 725534

African (AFR) AF: 0.0278 AC: 931 AN: 33448

American (AMR) AF: 0.0430 AC: 1924 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.0939 AC: 2452 AN: 26100

East Asian (EAS) AF: 0.000252 AC: 10 AN: 39690

South Asian (SAS) AF: 0.0972 AC: 8373 AN: 86150

European-Finnish (FIN) AF: 0.0873 AC: 4658 AN: 53368

Middle Eastern (MID) AF: 0.101 AC: 581 AN: 5756

European-Non Finnish (NFE) AF: 0.0777 AC: 86168 AN: 1108598

Other (OTH) AF: 0.0675 AC: 4066 AN: 60262

GnomAD4 genome AF: 0.0636 AC: 9673 AN: 152198 Hom.: 366 Cov.: 32 AF XY: 0.0628 AC XY: 4676 AN XY: 74416

African (AFR) AF: 0.0316 AC: 1311 AN: 41538

American (AMR) AF: 0.0584 AC: 894 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0985 AC: 342 AN: 3472

East Asian (EAS) AF: 0.000387 AC: 2 AN: 5172

South Asian (SAS) AF: 0.0891 AC: 430 AN: 4828

European-Finnish (FIN) AF: 0.0915 AC: 969 AN: 10588

Middle Eastern (MID) AF: 0.0884 AC: 26 AN: 294

European-Non Finnish (NFE) AF: 0.0812 AC: 5522 AN: 67990

Other (OTH) AF: 0.0711 AC: 150 AN: 2110

Alfa AF: 0.0750 Hom.: 838

Bravo AF: 0.0576

Asia WGS AF: 0.0240 AC: 83 AN: 3478

EpiCase AF: 0.0836

EpiControl AF: 0.0769

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	2	Pyridoxal phosphate-responsive seizures (2)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.37
CADD	Benign	11
DANN	Benign	0.82
PhyloP100		0.97
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs4378657; hg19: chr17-46023694; COSMIC: COSV107309012; COSMIC: COSV107309012;